The primary objective of the proposed research is to extend knowledge of the amount of genic variation in the house mouse (Mus musculus) by screening both inbred laboratory strains and wild (feral) populations for polymorphic structural variants (allozymes) of enzymes and other proteins that are not demonstrable by conventional techniques of gel electrophoresis. Allelic substitutions involving amino acid sequence changes that do not alter electrophoretic mobility of polypeptides will be detected and characterized by measuring thermostability, electrophoretic response to treatment with sulphydryl reagents, solubility in high-molar salt solutions, effects of urea and other general and specific inhibitors, rate constants and substrate affinities, and similar physicochemical properties other than net electrostatic charge. The research seeks to measure the degree of genetically determined structural heterogeneity among electrophoretic allozymes of a variety of proteins occurring primarily in erythrocytes and plasma, with the objective of more closely estimating the total amount of genic variation in the house mouse and the ratio of charge-modifying to other polymorphic amino acid substitutions. A comparison of frequencies and micro- and macrogeographic patterns of variation in allozymes characterized by electrophoretic mobility differences and those affecting other physicochemical properties will be undertaken to advance our understanding of the bases of maintenance of very high levels of molecular polymorphism in natural populations of mice, men, and other organisms.